A universal influenza vaccine by dual-domain fusion with a novel carrier protein

一种与新型载体蛋白双结构域融合的通用流感疫苗

• 批准号: 8057787
• 负责人: Yawei Ni
• 金额: $ 30万
• 依托单位: KJ BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-22 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8057787
• 关键词: Adjuvant; Amino Acids; Animal Model; Animals; Antibodies; Antigens; Archaea; Bacteria; Carrier Proteins; Cells; Chimeric Proteins; Clinical Research; DNA-Binding Proteins; Development; Epidemic; Escherichia coli; Evaluation; Ferrets; Future; Generations; Goals; Heating; High temperature of physical object; Hour; Immune response; Industry; Influenza; Influenza A virus; Influenza B virus; Life; Measures; Membrane Proteins; Modeling; Mus; Mutation; Peptides; Phase; Positioning Attribute; Primates; Process; Property; Reaction; Recombinant DNA; Refrigeration; Resistance; Stress; Sulfolobus solfataricus; Surface; Surface Antigens; System; Techniques; Tertiary Protein Structure; Testing; Toxicology; Vaccines; Virus; aluminum sulfate; base; hyperthermophile; immunogenicity; influenza epidemic; influenza virus strain; influenza virus vaccine; influenzavirus; meetings; nanoparticle; novel; pandemic disease; pre-clinical; protective effect; research study; vaccine candidate; vaccine development; vaccine effectiveness

DESCRIPTION (provided by applicant): The rapid genetic changes of influenza viruses continue to cause great difficulties with current strain- specific influenza vaccines in providing adequate control for influenza epidemics and effective countermeasures against pandemics. Thus, a universal vaccine that targets conserved antigen domains and provides protection against all influenza virus strains is urgently needed. The M2e and fusion peptide (FP) are the two most highly conserved antigen domains found in influenza virus surface proteins. The M2e (24 amino acids) is conserved among all influenza A viruses and the FP (14 amino acids) is conserved among both influenza A and B viruses. Current development efforts for a universal vaccine have primarily focused on single-domain constructs based on M2e. As the conserved antigen domains consist of just short peptides, an effective multivalent protein carrier system is critical in enhancing vaccine effectiveness and product feasibility with respect to manufacturing, storage, distribution, and use. KJ Biosciences aims to meet this urgent need by developing a novel dual-domain universal influenza vaccine incorporating both M2e and FP antigen domains that will provide protection against all influenza A and B viruses and can therefore be used to control influenza epidemics as well as pandemics. It will be produced by dual-domain fusion with a unique nanoparticle protein carrier that has both N- and C-termini exposed on the surface for antigen attachment. The vaccine product can also be stabilized at room or higher temperatures based on the unique properties of the carrier protein. A thermostable vaccine will significantly reduce the logistical requirements for storage, distribution, and use of the vaccine product, which is especially important when facing a pandemic. The goal of this proposal is to continue to develop this dual-domain universal influenza vaccine based on the promising results from preliminary studies. The proposed studies have two specific aims. Specific aim 1: Generation and characterization of the fusion proteins. Dual-domain fusion proteins with M2e and FP antigen domains arranged in different positions will be generated with the nanoparticle carrier protein by recombinant DNA techniques. They will be tested to demonstrate nanoparticle formation, reaction with antibodies specific to the antigen domains, and stability at room or higher temperatures. Specific aim 2: Immunogenicity and protection. Selected dual-domain fusion protein vaccine candidate (s) will be tested in animal models to demonstrate that the vaccine candidate can induce specific antibodies and protect animals against challenge with live influenza viruses. Completion of these two specific aims will form the basis for further preclinical immunogenicity evaluation and process development to produce the candidate vaccine for toxicology and phase I clinical studies. Successful development of this vaccine will afford an effective measure for controlling influenza epidemics and also greatly enhance our ability to respond to future pandemics. PUBLIC HEALTH RELEVANCE: The rapid changes of influenza viruses continue to cause great difficulties with current strain-specific influenza vaccines in providing adequate control for influenza epidemics and effective countermeasures against pandemics. This project aims to develop a novel dual-domain universal influenza vaccine that can be used to control seasonal epidemics as well as pandemics and also be rapidly produced and distributed without refrigeration. This vaccine is made possible by incorporation of two highly conserved influenza antigen domains using a unique carrier protein from bacteria.

描述（由申请人提供）：流感病毒的快速遗传变化继续给目前的菌株特异性流感疫苗在提供对流感流行的充分控制和对大流行的有效对策方面造成很大困难。因此，迫切需要一种针对保守抗原结构域并对所有流感病毒株提供保护的通用疫苗。M2e和融合肽（FP）是流感病毒表面蛋白中发现的两个高度保守的抗原结构域。M2e（24个氨基酸）在所有甲型流感病毒中保守，FP（14个氨基酸）在甲型流感病毒和乙型流感病毒中都保守。目前通用疫苗的开发工作主要集中在基于M2e的单一结构域构建体上。由于保守抗原结构域仅由短肽组成，因此有效的多价蛋白载体系统对于提高疫苗的有效性和产品在制造、储存、分销和使用方面的可行性至关重要。